Osmate esters of 20-cyanopregnanes and process



Patented Feb. 13, 1951 OSMATE ESTERS OF ZU-CYANOPREGNANES AND PROCESSLewis Hastings Sarett, Princeton, N. J., assignor to Merck & 00., Inc.,Rahway, N. J a corporation of New Jersey No Drawing. ApplicationFebruary 18, 1949, Serial No. 77,267

14 Claims. 1

This invention is concerned generally with novel steroid compounds andwith processes for preparing them. More particularly it relates to17,20-osmate esters of 17,20-dihydroxypregnane compounds which have acyano substituent attached to the -20 carbon atom, and to processes ofpreparing these compounds from the corresponding A -20-cyano-pregnenecompounds.

This application is a continuation-in-part of my copending application,Serial No. 778,465, filed October 7, 1947 which, in turn, is acontinuationin-part of my co-pending application Serial No. 773,525,filed September 11, 194.7. I have disclosed in these parent applicationsthat, when these novel 17,20-osmate esters of17,20-dihydroxy-ZO-cyano-pregnane compounds are treated with ahydrolyzing agent, there is obtained the corresponding 17(a)-hydroxy-20-keto-pregnane compound. The l7-hydroxy group, introducedaccording to this novel method, is obtained, surprisingly enough, inonly one isomeric form, namely the a or natural configuration; i. e.,the a hydroxy groupings in the compounds thus obtained have the samestereo-chemical configuration as that present in many of thenaturallyoccurring adrenal hormones. This is of especial interest in thepreparation of pregnene-l-diol- 17-(a) ,21-trione-3,l1,20 KendallsCompound E) and its Zl-acyl derivatives. These compounds are importantas adrenal hormones or in therapy requiring adrenal hormone typecompounds. They are further useful in the synthesis or" similar hormonesand compounds.

These 17,20-osmate esters of 17,20-dihydroxypregnane compounds whichhave a cyano substituent attached to the 0-20 carbon atom possess anadditional unexpected and valuable property; i. e., the osmate esterlinkages in these compounds are, surprisingly enough, very stable tooxidizing agents. It is thus possible to react oxidizing agents with17,20-osmate esters of 17,20- dihydroxy-20-cyano-pregnane compoundshaving one or more nuclear hydroxy substituents, thereby oxidizing thenuclear hydroxy substituents to keto radicals without affecting theosmate ester linkages. When the resulting nuclear keto-substituted17,20-osmate-esters of 17,20-dihydroxy- 20-cyano-pregnane compounds arehydrolyzed, there are obtained the corresponding 17(a)-hydroxy-ZO-keto-pregnane compounds containing at least one nuclear ketosubstituent. These compounds are of especial importance in preparingadrenal hormone type compounds, since such compounds ordinarily have oneor more keto 2 substituents attached to the perhydrophenanthrenenucleus.

The fact that the herein described ZO-cyano- 17,20-osmate esters arestable to oxidizing agents is indeed remarkable since, in 17,20-osmateesters of 17,20-dihydroxy-pregnane compounds which do not have aZO-cyano substituent, the osmate ester linkages are ordinarily extremelysensitive to oxidizing agents, such as chromic acid. For example, whenthe 17,20-osmate ester of 3(a), 17,20-trihydroxy-1l-keto-pregnane isoxidized with chromic acid under conditions operative for the oxidationof the corresponding ZO-cyano derivatives, none of the corresponding17,20-osmate ester of 3,11-diketo-17,20-dihydroxy-pregnane is formed.When the 17,20-osmate of 3(a),17-20 trihydroxy-l1-keto-20-cyano-pregnaneis reacted with chromic acid the corresponding 17,20-osmate ester of3,1l-dileto-l7,20-dihydroxy-20-cyanopregnane is, however, obtained andwith no appreciable loss in yield due to destructive oxidation I of the17,20-osmate grouping.

(commonly known as These novel and valuable 17,20-osmate esters of17,20-dihydroxy-20-cyano-pregnane. compounds are prepared by reactingosmium tetroxide with the corresponding A -20-cyano-preg nene compound.Examples of these A -20cyanopregnene starting materials are: A-20-cyanopregnene, A -3(a) -acy1oXy-20cyano-pregnene, A"3-acetoxy-20cyano-pregnene, A 3(a) -acyloxy-ll-keto20-cyano-pregnene, A3(a) ,21-diacyloxy-ZO-cyano-pregnene, A -3(a.),21-diacetoxy-20-cyano-pregnene, A -3-acetoxy-11-keto-ZO-cyano-pregnene, A -3-benzoxy-ll-keto-ZO- cyano-pregnene, A-3,1Z-diacyloxy-ZO-cyanopregnene, A-3,1221-triacetoxy-ZO-cyano-pregnene, A -3(a),21-diacyloxy-ll-keto-ZD-cyanopregnene, A -3 (a),Zl-diacetoxy-ll-keto-ZO-cyano-pregnene, A 3(a)-hydroxy-20-cyano-pregnene, A -3(a) -hydroxy-11-keto-20-0yano-pregnene,A 3(a) 21-dihydroxy-20-cyano-pregnene, A-3-l2-dihydroxy-20-cyano-pregnene,

A -3,1221-trihydroxy-20-cyano-pregnene, A 3(a),2l-dihydroxy-11-keto-2Ocyano pregnene, A -3-keto-20-cyano-pregnene, A -3,11-diketo-20-cyano-pregnene, A -3,12-diketo-20-cyanopregnene, A-3,11-diketo-20-cyano-21-acetoxypregnene, A -3 (a)-hydroxy-20-cyano-21-acetoxy-pregnene, A 13-12-dihydroxy-20-cyano-21-acetoxy-pregnene, A -3 (a) -hydroXy-11-keto-20-cyano-2l-acetoxy-pregnene, and the like. These starting materials can beprepared according to the procedures described in my co-pendingapplications Serial No. 778,465, filed October 7, 1947 and Serial No.77,268, filed February 18, 1949,

The reaction between the A -20-cyano-pregnene compound and osmiumtetroxide is ordinarily carried out in the presence of pyridine and asolvent for the reactants, as for example, benzene. The reaction isconveniently conducted at room temperature under which condition thereaction is substantially complete in about 15 hours. The 17,20-osmateester, produced according to this procedure can be recovered byevaporating the reaction solution to dryness, preferably under reducedpressure.

The 17,20-osmate esters of 17,20-dihydroxy- ZO-cyano-pregnane compoundsproduced ,according to this reaction include: the 17,20-osmate ester of17,20-dihydroxy-20-cyano-pregnane, the 17,20-osmate ester of3(a)-acyloxy-17,20-dihydroxy 20 cyano pregnane, the 17,20 osmate esterof 3(a) acyloxy 11 keto 17,20 -:di hydroxy-20-cyano-pregnane, the17,20-osmate .ester of 3(a),21 diacyloxy 17,20 dihydroxy20-cyano-pregnane, the 17,20-osmate ester of .3(a),21 diacetoxy 17,20dihydroxy 20 cyano-pregnane, the 17,20-osmate ester of 3- acetoxy llketo 17,20 dihydroxy 20 cyano-pregnane, the 17,20-osmate ester of 3-vbenzoxy l1 keto 17,20 dihydroxy 20 cyano-pregnane, the 17,20-osmateester of 3,12- diacyloxy 17,20 dihydroxy 20 cyano nane,the 17,20-osmateester of 3 (a) ,21-diacy1oxy- 11 keto 17,20 dihydroxy 20 cyano pregnane,the 17,20-osmate ester of 3(a),21-

diacetoxy 11 keto 17,20 dihydroxy 20 em cyano pregnane, the 17,20 osmateester of 3(a),17,20 trihydroxy 20 cyano pregnane, the 17,20-osmate esterof 3(a),17,20-trihydroxy- '11 -'keto 20 cyano pregnane, the 17,20

osmate ester 20-cyano-pregnane, the 17,20-osmate ester of 3,12,17,20tetrahydroxy 20 cyano pregnane, the 17,20-osmate ester of3,12,17,20,21-penta- 'hydroxy 20 cyano pregnane, the 17,20 osmate esterof 3(a) ,17,20,21 tetrahydroxy- 11 keto-20-cyano pregnane, the17,20-osmate ester of 3 keto 17,20 dihydroxy 20 cyano pregnane, the17,20-osmate ester of 3,11-diketo- 17,20 dihydroxy 20 cyano pregnane,the 17,20 osmate ester of 3,12 diketo 17,20

dihydroxy 20 cyano pregnane, the 17,20

osmate ester of 3,11 diketo 17,20 dihydroxy 20 cyano 21 acetoxypregnane, the 17,20 osmate ester of 3(a),1'7,20 trihydroxy 20 cyano 21acetoxy pregnane, the 17,20 osmate ester of 3,12,17,20 tetrahydroxy 20cyano 21 acetoxy pregnane, the 17,20 osmate ester of 3(a),17,20trihydroxy I1 keto 20 cyano 21 acetoxy pregnane, and the he.

Of particular interest are those 17,20-osmate esters of 17,20 dihydroxy20 cyano pregnane compounds having at least one nuclear hydroxysubstituent. In view of the stability to oxidizing agents possessed bythe osmate ester linkages in these compounds, they can be oxidized toproduce the corresponding 17,20-osmate ester of 17,20- dihydroxy 20cyano pregnane compounds in which the nuclear hydroxy substituents havebeen oxidized to keto radicals. For example, instead of preparing the17,20-osmate ester of 3- keto 17,20 dihydroxy 20 cyano pregnane byreacting osmium tetroxide with A -3-keto-20- cyano-pregnene, thiscompound can be prepared by reacting the 17,20-osmate ester of3,17,20-trihydroxy 2O cyano pregnane with an oxidizing pregnane, the17,20-osmate ester of 3,12,21-triacetoxy 17,20 dihydroxy 20 cyano preg 3of 3(a),l7,20,2l tetrahydroxyagent; similarly, the 17,20-osmate ester of3,11- diketo 17,20 dihydroxy 20 cyano pregnane is obtained by reactingthe 17,20-osmate ester of 3(a),l7,20 trihydroxy 11 keto 20 cyanopregnane with an oxidizing agent; oxidation of the'l'LZO-osmate esterio'f 3,12,17,20-tetrahydroxy- 20-cyano pregnane gives the 17,20-osmateester of 3,12 diketo 17,20 dihydroxy 20 cyano pregnane; oxidation of the17,20-osmate ester of 3(a),l7,20 -'trihydroxy 11 keto 20 cyano 21acetoxy pregnane gives the 17,20 osmate .ester of 3,11 diketo 17,20dihydroxy 20 cyano .21 -jacetoxy pregnane; and the like.

"The procedures indicated above are described in detail in my co-pendingapplication Serial No. 76,205, filed February 12, 1949.

The following examples illustrate methods of carryingout the presentinvention but it is to be understood that these examples are given byway .of illustration and not of limitation.

Example .1

196 mg. of A" 3,11 diketo 20 cyanopregnene (M. P. ZZZ-230 C.)is'dissolved in 2 cc. of benzene and 200 mg. of osmium tetroxide and "96mg. of pyridine are added to this solution. The resulting solution isallowed to stand at room temperature for-approximately 19 hours andthenevaporated to dryness in vacuo to produce the 17,20 osmate-ester of 3,11--diketo 17,20 di hydroxy-ZO-cyano-pregnane.

Example 2 1.0g. of A -3,11-diketo-20-cyano-2l -acetoxypregnene (M. P.-1'89-190-C.) is dissolved in 10 'cc.of benzene and the-solution istreated with "1.0 g. of osmium tetroxide and 0.43 g. of pyridine. Afterstanding at room temperature for'18 hours, the resulting solution isevaporated to dryness in vacuo to produce 'the 17,'20-osmate ester of3,11 diketo 17,20-dihydroxy-20-cyano-21-acetoxy-pregnane.

When A" 3,11-diketoe20-cyano 2l hydroxy- .pregnene (M. P. 263-265 C.) is--substituted for the 21-acety1 derivative in the foregoingprocedure,'the product obtained is the -17 ,20-osmate ester of 3,11diketo 17,20,21-trihydroxy-20- cyano-pregnane.

Example 3 'About 1.65 g. of A -3(a)-acetoxy11-keto-2'0- cyano-pregnene(M. P. '194-'195'C.) is dissolved in 1'6 ccuof benzene and-about 1.70 g.of osmium tetroxide and 0.75 cc. of pyridine are added to this solution.The resulting solution is allowed to stand at room temperature forapproximately 20 hours and then evaporated to dryness in vacuo "toproduce the 17,20-osmate ester of 3(a)-ace toxy 11 keto 17,20 dihydroxy20 cyano pregnane.

Example 4 ture overnight, thereactionsolution is evaporated to drynessunder reduced pressure to produce the 17,20-osmate ester of3(a).,21-diacetoXy-11eketo- 17,20-dihydroxye20-cyano-pregnane.

Example 5 429 mg. of A -3 (a)--hydroxy-11-keto-20-cyano-2.1-acetoxy-pregnene is dissolved .in 41 cc. of benzene and 600 mg. ofosmium tetroxide .and 0.30 cc. of pyridine is added to this benzenesolution.

The resulting mixture is allowed to stand at room temperature for about15 hours. The reaction solution is then evaporated to dryness in vacuoto produce the 17,20-osmate ester of 3(a),17,20- trihydroxy 11 keto 20cyano 21 acetoxypregnane.

Example 6 The osmate ester, prepared as described in Example 5, isdissolved in 5 cc. of 90% acetic acid and. this solution is treated withcooling with 1.05 cc. of acetic acid containing 3.52 milliequivalents ofsulfuric acid. A solution containing 250 mg. of chromic acid in 4.4 cc.of 90% acetic acid is added to the solution of the osmate ester and theresulting solution is allowed to stand at room temperature for 30minutes. 2 cc. of methanol is added to the reaction mixture and theresulting mixture is poured into a suspension of 5 gins. of potassiumbicarbonate in 20 cc. of water. The resulting neutralized mixture isevaporated to dryness under reduced pressure, to produce the17,20-osmate ester of 3,11-diketo- 17,20dihydroxy-20-cyano-2l-acetoxy-pregnane. This compound can also beprepared by treating A -3,11 diketo 20-cyano-2l-acetoxy-pregnene withosmium tetroxide as described in Example 2.

Example 7 1 g. of A -3(a) -hydroxy-l1-keto-20-cyanopregnene is dissolvedin 10 cc. of benzene and to this solution is added 1.0 g. of osmiumtetroxide and 0.6 cc. of pyridine. The resulting mixture is allowed tostand at room temperature for about hours. The reaction mixture is thenevaporated to dryness under reduced pressure to produce the 17,20-osmateester of 3(a) -hydroxy- 11-keto-17,20dihydroxy-20-cyano-pregnane.

Example 8 The osmate ester, prepared as described in Example 7, isdissolved in 10.5 cc. of acetic acid and 2.21 cc. of acetic acidcontaining 3.52 milliequivalents of sulfuric acid per cc. is added tothis solution. The resulting solution is cooled to 15 C., 9.2 cc. of 90%acetic acid containing 420 mg. of chromic acid is added thereto, and theresulting mixture is allowed to stand for 1 hour. About 4 cc. ofmethanol is added to the reaction mixture and the mixture is poured into4.0 cc. of water containing 31.5 g. of potassium bicarbonate. Theaqueous mixture is evaporated to dryness under reduced pressure, and ata temperature of 30 C., to produce the 17,20-osmate ester of3,11-diketo-17,20-dihydroXy-20-cyanopregnane. This compound can also beprepared by treating A -3,11-diketo--cyano-pregnene with osmiumtetroxide as described in Example 1.

Various changes may be made in the carrying out the present inventionwithout departing from the spirit and scope thereof. Insofar as thesechanges and modifications are within the purview of the annexed claims,they are to be considered as part of my invention.

I claim:

1. 17,20-osmate esters of 1'7,20-dihydroxy-pregnane compounds having acyano radical attache to the C-20 carbon atom.

2. 17,20-osmate esters of 17,20-dihydroxypregnane compounds having acyano radical attached to the 6-20 carbon atom, and having at least onenuclear hydroxy substituent.

3. 1l,20-osmate esters of 17,20-dihydroxypregnane compounds having acyano radical attached to the C-20 carbon atom, and having at least onenuclear keto substituent.

4. The 17,20-osmate ester of 3,l1-diketo-17,20-dihydroxy-20-cyano-pregnane.

5. The 17,20-osmate ester of 3,11-diketo-17,20-dihydroxy-20-cyano-2l-acetoxy-pregnane.

6. The 17,20-osmate ester of 3(a), 21-diacetoxy-11-keto-1'7,20-dihydroxy20 cyano pregname.

7. The 17,20-0smate ester of 3(a), 17,20-trihydroxy-ll-keto-ZO-cyano 21acetoxy pregnane.

8. The 17,20-osmate ester of 3(a)-hydroxy-11-keto-17,20-dihydroxy-ZO-cyano-pregnane.

9. The process of preparing 17,20-osmate esters of17,20-dihydroXy-pregnane compounds having a cyano radical attached tothe C-20 carbon atom, which comprises reacting osmium tetroxide With a A-20-cyano-pregnene compound.

10. The process of preparing 17,20-0smate esters of17,20-dihydroxide-pregnane compound having a cyano radical attached tothe 0-20 carbon atom and having at least one nuclear hydroxysubstituent, which comprises reacting osmium tetroxide with a nuclearhydroxylated A -ZO-cyanO-pregnene compound.

11. The process of preparing 17,20-osmate esters of17,20-dihydroXy-pregnane compounds, having a cyano radical attached tothe C-20 carbon atom and having at least one nuclear keto substituent,Which comprises reacting osmium tetroxide with a nuclearketo-substituted A -20- cyano-pregnene compound.

in the presence of pyridine.

LEWIS HASTINGS SARETT.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date Butenandt Dec. 9, 1941

1. 17,20-OSMATE ESTERS OF 17,20-DIHYDROXY-PREGNANE COMPOUNDS HAVING ACYANO RADICAL ATTACHED TO THE C-20 CARBON ATOM.